Graft-versus-host disease (GVHD) is the major complication of allo-HSCT. GVHD in both the acute and chronic forms accounts for a high degree of mortality and morbidity, and remains the primary barrier to successful outcomes of this potentially curative therapeutic option. While GVHD is associated with beneficial and powerful graft-versus-tumor (GVT) effects when allo-HSCT is used to treat certain malignancies such as leukemia or lymphoma, GVHD is particularly undesirable when allo-HSCT in employed as a treatment for other non-malignant conditions. Traditionally, GVHD is divided into acute and chronic forms. Acute GVHD has been arbitrarily defined as occurring during the first 100 days post transplant, whereas chronic GVHD develops after the first 100 days. While this classification has been the "gold standard" for decades, it fails to account for the wide range of pathologies associated with GVHD, an issue that has become particularly relevant when considering the impact reduced intensity conditioning regimens have had on the kinetics of GVHD induction. Perhaps more importantly, given the limited advances made in the treatment and prevention of clinical GVHD, the traditional definition does little with respect to improving our understanding of the pathophysiologic mechanisms of post-HSCT complication. Acute GVHD is mediated predominately by cellular (CD4+ and/or CD8+) effectors, (with emphasis on the cytokines IFN and TNF, ultimately results in epithelial apoptosis and ) target organ injury, and therefore could be classified as cytotoxic (henceforth referred to as Cyt GVHD). Chronic GVHD, on the other hand, can be associated with autoantibody production (lupus-like), or in part, with overproduction of collagen by fibroblasts in skin, lung and other tissues similar to what is seen in the autoimmune disease scleroderma. Our mid to long-term goal is to examine the role of innate immunity in shaping the T cell response that initiates GVHD and to see how host conditioning influences these interactions. To this end, we plant to utilize both in vitro and in vivo studies to examine interactions between micro-environment, innate immunity, and dendritic cell (DC) populations that drive and shape the development of GVHD. Our central hypotheses is as follows: While in that in the absence of conditioning, constitutive interactions between specific DC subsets and donor T cells are sufficient to promote development of Scl GVHD, host conditioning promotes novel DC-T cell interactions that directly modulates the type of GVHD that ensues. We plan to test the central hypothesis by pursuing the following specific aims: Aim 1: Identify the specific DC subsets and cognate interactions between host DCs and donor T cells that are responsible for the development of Scl GVHD Aim 2: Determine the mechanisms by which host conditioning and specific DC subsets modulate effector T cell phenotypes and shape the type of GVHD that ultimately develops PUBLIC HEALTH RELEVANCE: Graft-versus-host disease is a major complication of hematopoietic cell transfer that is often the treatment of last resort for several types of hematological cancer. Despite development of new treatments over the last decade, the morbidity and mortality rate of GVHD is still very high. The purpose of this study is to understand the basic triggering mechanisms of two common variants of GVHD with the hopes of identifying new targets for therapeutic intervention.